Our principal objective is to define molecular and biophysical mechanisms of associative learning and memory. Emphasis is placed on learning and memory which can be related to human cognition. Ultimate goals are to arrive at clinically meaningful interventions and to design and construct artificial intelligence which has advanced learning and memory capabilities. With human cognitive function as the principal frame of reference, the research focuses on associative processes (such as Pavlovian conditioning) rather than nonassociative behavioral modifications (such as sensory adaptation, habituation, arousal, and sensitization). The biological basis of learning and memory is of interest at several levels of complexity: behavior, neuronal systems, neuronal architecture and membranes and molecular transformations. To reconstruct the physiology involved (and to model it in artificial contexts) it is necessary to use both "simple system" preparations such as the nudibranch mollusk Hermissenda crassicornis as well as "complex system" preparations such as rabbits and rats. The molluscan work has yielded the first unequivocal biological record of an associative memory. This record consists of persistent transformations of specific ionic channels. Because these records have been found within the membranes of identified single neurons, it is now possible to define biochemical pathways regulating such long-term membrane modifications as well as to analyze how this biological memory record is expressed by the integrative functions of an entire neuronal system. The work on the vertebrate brain offers two essential opportunities. First, the generality of mechanisms determined for much less evolved species can be tested. Remarkably, the same ionic channel transformations were shown to record associative memory in the rabbit as were found in Hermissenda. Rabbit and now rat neural systems have also provided sufficient quantities of tissue so that conditioning-specific alterations of critical enzymatic (e.g., protein kinase C) pathways which control membrane excitability have recently been demonstrated. Furthermore, identical G protein substrates which regulate similar K+ channels, intraaxonal transport, mRNA turnover, and architecture of dendritic trees, undergo memory-specific modification in mollusks and mammals. Such biophysical and molecular parallels in mechanisms of memory storage suggest the possibility of general cellular principles of memory storage significant for human physiology and pathophysiology as well. These identified conserved mechanisms of associative memory are guiding a program to uncover targets of dysfunction in Alzheimer,s disease for purposes of diagnosis, therapy, and prevention.